The present invention relates to novel compounds, methods of preparing these compounds, and pharmaceutical compositions comprising these compounds. These compounds are carbamate prodrugs that convert to active inhibitors of the IMPDH enzyme in vivo. The compounds and pharmaceutical compositions of this invention are particularly well suited for activation and subsequent inhibition of the IMPDH enzyme activity. Consequently, these prodrugs may be advantageously used as therapeutic agents for IMPDH mediated processes. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds and compositions of this invention.
IMPDH (EC 1.1.1.205) is an enzyme involved in the de novo synthesis of guanosine nucleotides. The synthesis of nucleotides in organisms, in general, is required for the cells in those organisms to divide and replicate. Nucleotide synthesis in mammals may be achieved through one of two pathways: the de novo synthesis pathway or the salvage pathway. Different cell types use these pathways to different extents. IMPDH catalyzes the NAD-dependent oxidation of inosine-5xe2x80x2-monophosphate (IMP) to xanthosine-5xe2x80x2-monophosphate (XMP)[Jackson R. C. et. al., Nature, 256, pp. 331-333, (1975)].
IMPDH is ubiquitous in eukaryotes, bacteria and protozoa [Y. Natsumeda and S. F. Carr, Ann. N.Y. Acad., 696, pp. 88-93 (1993)]. The prokaryotic forms share 30-40% sequence identity with the human enzyme. Two isoforms of human IMPDH, designated type I and type II, have been identified and sequenced [F. R. Collart and E. Huberman, J. Biol. Chem., 263, pp. 15769-15772, (1988); Y. Natsumeda et. al., J. Biol. Chem., 265, pp. 5292-5295, (1990)]. Each is 514 amino acids, and they share 84% sequence identity.
The de novo synthesis of guanosine nucleotides, and thus the activity of IMPDH, is particularly important in B and T-lymphocytes. These cells depend on the de novo, rather than salvage pathway to generate sufficient levels of nucleotides necessary to initiate a proliferative response to mitogen or antigen [A. C. Allison et. al., Lancet 2(7946), pp. 1179-1183, (1975) and A. C. Allison et. al., Ciba Found. Symp., 48, pp. 207-224, (1977)]. Thus, IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
In addition to its role in the immune response, it is also known that IMPDH plays a role in other metabolic events. Increased IMPDH activity has been observed in rapidly proliferating human leukemic cell lines and other tumor cell lines, indicating IMPDH as a target for anti-cancer as well as immunosuppressive chemotherapy [M. Nagai et. al., Cancer Res., 51, pp. 3886-3890, (1991)]. IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH, such as MPA or rapamycin, may be useful in preventing restenosis or other hyperproliferative vascular diseases [C. R. Gregory et al., Transplantation, 59, pp. 655-61 (1995); PCT publication WO 94/12184; and PCT publication WO 94/01105].
Additionally, IMPDH has been shown to play a role in viral replication in some viral cell lines. [S. F. Carr, J. Biol. Chem., 268, pp. 27286-27290 (1993)]. Analogous to lymphocyte and tumor cell lines, the implication is that the de novo, rather than the salvage, pathway is critical in the process of viral replication.
Mycophenolic acid (MPA) and some of its derivatives have been described as inhibitors of IMPDH [U.S. Pat. Nos. 5,380,879 and 5,444,072 and PCT publications WO 94/01105 and WO 94/12184]. These compounds are potent, non-competitive, reversible inhibitors of human IMPDH type I (Ki=33 nM) and type II (Ki=9 nM). MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen [A. C. Allison et. al., Ann. N. Y. Acad. Sci., 696, pp. 63-87, (1993)]. MPA is characterized by undesirable pharmacological properties, however, such as gastrointestinal toxicity and poor bioavailability. [L. M. Shaw, et. al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995)].
Mycophenolate mofetil (MMF), a prodrug which quickly liberates free MPA in vivo, has been approved to prevent acute renal allograft rejection following kidney transplantation. [L. M. Shaw, et. al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995); H. W. Sollinger, Transplantation, 60, pp. 225-232 (1995)]. Several clinical observations, however, limit the therapeutic potential of this drug. [L. M. Shaw, et. al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995)]. First, the active drug, MPA, is rapidly metabolized to the inactive glucuronide in vivo. [A. C., Allison and E. M. Eugui, Immunological Reviews, 136, pp. 5-28 (1993)]. The glucuronide then undergoes enterohepatic recycling causing accumulation of MPA in the gastrointestinal tract where it cannot exert its IMPDH inhibitory activity on the immune system. This effectively lowers the drug""s in vivo potency, while increasing its undesirable gastrointestinal side effects. In addition, MMF has inherent drawbacks as a prodrug. MMF is the morpholinoethyl ester of MPA. In vivo MMF is deesterified to MPA, but this hydrolysis can occur over a wide pH range in an aqueous environment. Therefore, it is difficult to control the time and location of activation of the drug.
Urea derivatives, which are more effective than MPA as inhibitors of IMPDH, have recently been described in U.S. Pat. No. 5,807,876 and in co-pending continuation applications 08/801,780 and 08/832,165, herein incorporated by reference. These compounds exhibit both an increased overall therapeutic effect and decreased deleterious side effects in their inhibition of IMPDH and in their use as compositions. But the aqueous solubility of these compounds is less than optimum.
The aqueous solubility of an organic molecule can impact its absorption following oral administration. For example, the oral administration of a highly hydrophobic compound can very easily result in poor absorption due to precipitation in the gastrointestinal tract. Formulation of such hydrophobic compounds with surfactants and complexing agents can improve the aqueous solubility of these compounds, but this method becomes more impractical as the aqueous solubility decreases. However, chemical modification of a drug into a bio- or chemically-reversible prodrug can confer temporary aqueous solubility to the drug substance that allows absorption following oral administration.
For orally administered prodrugs, the drug substance""s kinetic solubility in neutral to acidic media is of most interest. In most cases, the kinetic solubility in these media is higher than the corresponding thermodynamic solubility. Therefore, it is advantageous to utilize this transient increase in solubility that immediately follows the conversion of the prodrug to the drug substance. The time it takes to reach thermodynamic equilibrium will vary from compound to compound and can only be determined experimentally. A strategy for creating prodrugs of IMPDH inhibitors that exploits the compound""s kinetic solubility would be advantageous. Alternatively, a prodrug which liberates the drug substance as a fine dispersion intestinally may also improve its oral absorption, with smaller particle sizes being preferred.
Prodrug strategies which rely on intramolecular cyclization/transacylation to liberate a drug substance and a lactam derivative have been described where the liberated drugs are alcohols, phenols, and primary and secondary amines. For alcohols [Saari, et al, J. Med. Chem., 33, pp. 2590-2595 (1990)] and phenols [Saari, et al, J. Med. Chem., 33, pp. 97-101 (1990)], the facility of cyclization and hydroxyl liberation is a consequence of the lower pKa of the resulting leaving group (pKa 10-16). Such prodrugs are easily prepared by known methods which offer a reasonable amount of synthetic flexibility allowing one to modulate the rate of prodrug to drug conversion. The rates of liberation for cyclizing alcohol and phenol prodrugs are sensitive to pH. For amines [Borchhardt, et al, Pharm. Sci., 86, pp. 765-767 (1997)] strategies have been developed which utilize cyclization of highly constrained systems as well as the use of additional functionalization in the form of aminals. Such measures are taken to overcome the poor ability of alkyl amines to serve as leaving groups (pKaxe2x89xa730). These methods, however, are inadequate for the formation of prodrugs of drugs lacking alcohols, phenols, or primary and secondary amines.
Thus, there is a need for prodrugs of potent IMPDH inhibitors. Desirable properties of these prodrugs would include better aqueous solubility with corresponding improved bioavailability, and the ability to be activated at particular times and locations in the body as needed. Such prodrug inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-vascular hyperproliferative agents and anti-viral agents. Specifically, such compounds may be used in the treatment of transplant rejection and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease, as well as in the treatment of cancer and tumors, such as lymphomas and leukemia, vascular diseases, such as restenosis, and viral replication diseases, such as retroviral diseases and herpes.
The present invention provides compounds, and pharmaceutically acceptable derivatives thereof, that are prodrugs of carbamate derivatives, described in U.S. Pat. No. 5,807,876, and in co-pending continuation applications Ser. Nos. 08/801,780 and 08/832,165, that function as inhibitors of IMPDH. The invention further provides a method for preparing pH-triggered, cyclizing prodrugs of drug substances comprising secondary carbamates. The carbamate prodrugs described herein can be selectively activated to produce an active compound and a non-toxic by-product. The release of the active compounds can modulated as a function of pH and rate of liberation, which in turn allows absorption to be more carefully controlled. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antibiotics, and immunosuppressants for the treatment or prophylaxis of transplant rejection and autoimmune disease. Additionally, these compounds are useful, alone or in combination with other agents, as therapeutic and prophylactic agents for antiviral, anti-tumor, anti-cancer, immunosuppressive chemotherapy and restenosis therapy regimens.
Specifically, the invention provides a compound of the Formula (I): 
wherein:
A is either B or is selected from:
(C1-C6)-alkyl, or (C2-C6)-alkenyl or alkynyl;
and A optionally comprises up to 2 substituents, wherein:
the first of said substituents, if present, is selected from R1 or B, and
the second of said substituents, if present, is R1; wherein:
each R1 is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, (C1-C4)-alkyl, (C2-C4)-alkenyl or alkynyl, or (CH2)n-W1; wherein n is 0, 1 or 2; R1 is optionally substituted with R5; and
W1 is selected from halogen, CN, NO2, CF3, OCF3, OH, S(C1-C4)-alkyl, SO(C1-C4)-alkyl, SO2(C1-C4)-alkyl, NH2, NH(C1-C4)-alkyl, N((C1-C4)-alkyl)2, N((C1-C4)-alkyl)R8, COOH, C(O)NH2, C(O)NH(C1-C4)-alkyl, C(O)N((C1-C4)-alkyl)2, xe2x80x94C(O)O(C1-C4)-alkyl or O(C1-C4)-alkyl; and
R8 is an amino protecting group;
B is selected from a monocyclic or a bicyclic, saturated or unsaturated or aromatic, ring system consisting of 5 to 6 members per ring, wherein each ring optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to any of said N, O, or S heteroatoms is optionally replaced with C(O); and each B optionally comprises up to 3 substituents, wherein:
the first of said substituents, if present, is selected from R1, R2, R4 or R5,
the second of said substituents, if present, is selected from R1 or R4, and
the third of said substituents, if present, is R1; wherein:
each R2 is independently selected from (C1-C4)-alkyl, or (C2-C4)-alkenyl or alkynyl; and each R2 optionally comprises up to 2 substituents, wherein:
the first of said substituents, if present, is selected from R1, R4 and R5, and
the second of said substituents, if present, is R1;
each R4 is independently selected from OR5, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6)2, OP(O)(OR6)2, SR6, SR5, S(O)R6, S(O)R5, SO2R6, SO2R5, SO2N(R6)2, SO2NR5R6, SO3R6 , C(O)R5, C(O)OR5, C(O)R6, C(O)OR6, NC(O)C(O)R6, NC(O)C(O)R5, NC(O)C(O)OR6, NC(O)C(O)N(R6)2, C(O)N(R6)2, C(O)N(OR6)R6, C(O)N(OR6)R5, C(NOR6)R6, C(NOR6)R5, N(R6)2, NR6C(O)R1, NR6C(O)R6, NR6C(O)R5, NR6C(O)OR6, NR6C(O)OR5, NR6C(O)N(R6)2, NR6C(O)NR5R6, NR6SO2R6, NR6SO2R5, NR6SO2N(R6)2, NR6SO2NR5R6, N(OR6)R6, N(OR6)R5, OP(O)(OR6)N(R6)2, and OP(O)(OR6)2;
each R5 is a monocyclic or a bicyclic, saturated or unsaturated or aromatic, ring system consisting of 5 to 6 members per ring, wherein each ring optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to said N, O or S maybe replaced with C(O); and each R5 optionally comprises up to 3 substituents, each of which, if present, is selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, (C1-C4)-alkyl, (C2-C4)-alkenyl or alkynyl, or (CH2)n-W1; wherein n is 0, 1 or 2;
and wherein any R5 heterocyclic ring in R5 is optionally benzofused;
each R6 is independently selected from H, (C1-C5)-alkyl, or (C2-C5)-alkenyl or alkynyl, and each R6 optionally comprises a substituent that is R5; and wherein
any carbon atom in any A, R2 or R6 is optionally replaced by O, S, SO, SO2, NH, or N(C1-C4)-alkyl;
D is selected from N(R9)xe2x80x94C(O)xe2x80x94N(R9), C(O)xe2x80x94N(R9), N(R9)xe2x80x94C(O), NR9xe2x80x94C(O)xe2x80x94C(R10)xe2x95x90C(R10);
each R9 is independently selected from hydrogen, (C1-C4)-alkyl, (C2-C4)-alkenyl or alkynyl, R5-substituted-(C1-C4)-alkyl, or R5-substituted-(C2-C4)-alkenyl or alkynyl; wherein
R9 is optionally substituted with up to 3 substituents independently selected from halo, hydroxy, nitro, cyano or amino;
each R10 is independently selected from R9, W4xe2x80x94[C1-C4-alkyl], W4xe2x80x94[C2-C4-alkenyl or alkynyl], R5-substituted-[W4xe2x80x94[C1-C4-alkyl]], R5-substituted-[W4xe2x80x94[C2-C4-alkenyl or alkynyl]], Oxe2x80x94R5, N(R9)xe2x80x94R5, Sxe2x80x94R5, S(O)xe2x80x94R5, S(O)2xe2x80x94R5, Sxe2x80x94C(O)H, N(R9)xe2x80x94C(O)H, or Oxe2x80x94C(O)H; wherein:
W4 is O, Oxe2x80x94C(O), S, S(O), S(O)2, Sxe2x80x94C(O), N(R9), or N(R9)xe2x80x94C(O); and wherein
each R10 is optionally and independently substituted with up to 3 substituents independently selected from halo, hydroxy, nitro, cyano or amino;
Z is C1-C10-alkylene, C2-C10-alkenyl or alkynyl, C1-C10 aryl-substituted alkyl, C2-C10 aryl-substituted alkenyl or alkynyl; wherein
up to 3 carbons may be replaced with xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94NR14; wherein
up to 3 xe2x80x94CH2xe2x80x94 groups may be replaced with xe2x80x94C(O)xe2x80x94; wherein
up to 5 hydrogen atoms in any of said alkyl, alkenyl, aryl, or alkynyl are optionally and independently replaced by R13 or R5;
R13 is halo, xe2x80x94OR14, xe2x80x94N(R14)2, xe2x80x94SR14, xe2x80x94S(O)R14, xe2x80x94S(O)2R14, xe2x80x94S(O)2OR14, xe2x80x94S(O)2N(R14)2, xe2x80x94N(R14)S(O)2N(R14)2, xe2x80x94OS (O)2N(R14)2, xe2x80x94NR14C(O)R14, xe2x80x94NR14C(O)OR14, xe2x80x94N(R14)C(O)N(R14)2, xe2x80x94N(R14)C(S)N(R14)2, xe2x80x94N(R14)C(NR14)N(R14)2, xe2x80x94C(O)R14, xe2x80x94C(O)OR14, xe2x80x94C(O)SR14, xe2x80x94C(O)N(R14)2, xe2x80x94C(NR14)N(R14)2, xe2x80x94C(S)OR14, xe2x80x94C(S)N(R14)2, xe2x80x94N(R14)P(O)(OR14)2, xe2x80x94OP(O)(OR14)2;
R14 is H, C1-C5-alkyl, C2-C5-alkenyl or alkynyl, aryl, or C1-C5 alkyl-aryl; wherein
up to 3 hydrogen atoms in R14 are optionally and independently replaced with a substituent that is R13; and wherein
any NR14, taken together with the nitrogen and a carbon adjacent to the nitrogen, optionally forms a 5-7 membered ring, wherein said ring optionally contains up to three additional heteroatoms selected from O, N, S, or S(O)2;
Y is xe2x80x94NH(R14);
RX is (C1-C6)-alkyl, wherein up to 4 hydrogen atoms in said alkyl are optionally and independently replaced by R20;
R20 is independently selected from halo, xe2x80x94OR21, xe2x80x94N(R22)2, xe2x80x94SR21, xe2x80x94S(O)R21, xe2x80x94S(O)2R21, xe2x80x94CN, or;
R21 is selected from hydrogen, xe2x80x94(C1-C6)-straight alkyl, xe2x80x94(C1-C6)-straight alkyl-R5, xe2x80x94C(O)xe2x80x94(C1-C6)-alkyl which is optionally substituted with R4, xe2x80x94C(O)xe2x80x94R5, or xe2x80x94(C1-C6)-straight alkylxe2x80x94CN;
each R22 is independently selected from hydrogen, xe2x80x94(C1-C6)-alkyl, xe2x80x94(C1-C6)-alkyl-R5, xe2x80x94(C1-C6)-straight alkylxe2x80x94CN, xe2x80x94(C1-C6)-straight alkylxe2x80x94OH, xe2x80x94(C1-C6)-straight alkylxe2x80x94OR21, xe2x80x94C(O)xe2x80x94(C1-C6)-alkyl, xe2x80x94C(O)xe2x80x94R5, xe2x80x94S(O)2xe2x80x94(C1-C6)-alkyl, or xe2x80x94S(O)2-R5; or two R22 moieties, when bound to the same nitrogen atom, are taken together with said nitrogen atom to form a 3 to 7-membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1 to 3 additional heteroatoms independently selected from N, O, or S;
Ry is selected from hydrogen, xe2x80x94CF3, xe2x80x94(C1-C6)-alkyl, xe2x80x94(C1-C6)-alkyl-R5, or xe2x80x94R5; or wherein RX and RY are optionally taken together with the carbon atom to which they are bound to form a monocyclic or a bicyclic, saturated or unsaturated or aromatic, ring system consisting of 5 to 6 members per ring, wherein each ring optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to said N, O or S maybe replaced with C(O); wherein 1 to 4 hydrogen atoms in said ring system are optionally replaced by xe2x80x94OC(O)CH3, xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)OH, xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)Oxe2x80x94(C1-C4)-alkyl, xe2x80x94Oxe2x80x94CH2xe2x80x94CN, or xe2x80x94Oxe2x80x94CH2xe2x80x94Cxe2x95x90CH2.
The invention also provides compositions comprising the compounds of this invention, as well as multi-component compositions comprising additional IMPDH-inhibitory compounds or prodrugs together with an immunosuppressant. The invention also provides methods of using the compounds of this invention, as well as other related compounds, for the inhibition of IMPDH. Finally, the invention also provides methods for producing carbamate drugs from secondary carbamate prodrugs.
The compounds of this invention, as well as those used in the methods of this invention demonstrate a different metabolic profile than MPA and its derivatives. Because of this difference, methods of this invention and the compounds used therein may offer advantages as therapeutics for IMPDH mediated disease. These advantages include increased overall therapeutic benefit and reduction in deleterious side effects.